tbuckley/cabot-search huggingface dataset:
Abstract P4-03-26: Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort
Authors: HuiChen Wu, Angelica Castano, Yuyan Liao, Regina Santella, David Brenner, Mary Beth Terry, Benjamin Tycko
Journal: Cancer Research (2023)

Abstract Breast cancer has increased dramatically in young women &amp;lt; 50 years in the US over the past decade. DNA methylation is a type of epigenetic change that plays an important role in cancer etiology by silencing tumor suppressor genes or DNA repair-related genes through hypermethylation or activating oncogenes through hypomethylation. Previous genome-wide association studies have suggested DNA methylation in blood is a potential epigenetic markers of breast cancer risk. In this study, we applied targeted methyl-seq to examine the DNA methylation profile in regulatory sequences of 57 known DNA repair pathway genes, together with 123 other genes, located in immune-related loci and genome-wide association peaks for breast cancer. We used a nested case-control design within the Breast Cancer Prospective Family Study Cohort (FroF-SC) and examined DNA methylation profile in DNA from the blood of breast cancer cases (N=293) and age-matched controls (N=327). In the preliminary data analysis, we observed that the methylation levels in 5 genes were statistically significantly different between cases and controls using Wilcoxon Rank Sum Test (Table 1). Some candidate loci show methylation values spanning a wide range (Std Dev) in both cases and controls, suggesting the presence of genotype-dependent allele-specific methylation (ASM). We then conducted generalized estimating equations (GEE model) adjusting for age at blood draw and calculated the odds ratios (ORs) and 95%CI for the association between methylation levels in the 90th and 10th percentiles of differentially methylated genes (90% vs 10% methylation) and breast cancer risk. The ORs (95% CI) from the GEE models were 1.26 (0.97, 1.63, p=0.08) for CD6, 1.27 (0.85, 1.91, p=0.24) for SDCCAG3, 1.12 (0.85, 1.48, p=0.40) for DCLRE1B, 1.29 (0.88, 1.90, p=0.20) for IP09, and 1.63 (1.08, 2.45, p=0.02) for GNPDA1 (Table 2). The associations were not different by age group. Our preliminary results suggest that DNA methylation measured in blood may be a biomarker of breast cancer susceptibility. Citation Format: HuiChen Wu, Angelica Castano, Yuyan Liao, Regina Santella, David Brenner, Mary Beth Terry, Benjamin Tycko. Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-26.
Abstract P6-11-04: Novel roles of Inosine Monophosphate Dehydrogenase 2 (IMPDH2) in TNBC doxorubicin resistance
Authors: Tatiane da Silva Fernandes, Anna Bianchi-Smiraglia
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is one of the major subtypes of breast cancer, being associated with the lowest survival rate after metastasis occurs. TNBC patients face limited therapeutic options, relying mostly on a combination of chemotherapies (anthracycline, taxanes and cyclophosphamide). However, around 40% of patients treated with chemotherapy relapse due to onset of chemoresistance, contributing to the dismal survival of this aggressive subtype. Therefore, understanding the molecular mechanisms underlying chemoresistance is critical to identify better therapeutic target options. Guanosine triphosphate (GTP) is important for several biological processes, including cell proliferation. We and others have shown that inosine 5’-monophosphate dehydrogenase 2 (IMPDH2), the rate limiting enzyme in the de novo synthesis of GTP, is important in migration and invasion of cancer, including TNBC, however the role it plays in chemoresistance remains to be elucidated. Our preliminary data revealed that IMPDH2 expression levels modulate doxorubicin sensitivity in different TNBC cell lines. Moreover, we have generated MDA-MB-231 cells that are resistant to doxorubicin (referred to as DoxoR), and revealed IMPDH2 to be upregulated in DoxoR cells, at both protein and mRNA levels as well as having higher activity. Consistently, DoxoR cells have ~50% more GTP than their naïve counterpart and, interestingly, are twice more sensitive to treatment with Ribavirin, a well-tolerated FDA approved IMPDH inhibitor, suggesting that Ribavirin could be repurposed for the treatment of chemoresistant TNBC. As expected, RNA sequencing of DoxoR cells revealed increased stemness properties when compared to naïve cells, which we confirmed experimentally in tumor sphere formation assays. Importantly, knockdown of IMPDH2 reverted the ability of DoxoR cells to form bigger tumor spheres, as well as reduced the IC50 of doxorubicin to that of naïve cells. Therefore, our data suggests that increased IMPDH2 and GTP levels in resistant setting could be a potential new vulnerability to be leveraged therapeutically to suppress and/or prevent the growth of chemoresistant lesions. Citation Format: Tatiane da Silva Fernandes, Anna Bianchi-Smiraglia. Novel roles of Inosine Monophosphate Dehydrogenase 2 (IMPDH2) in TNBC doxorubicin resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-04.
Associations between parental adherence to healthy lifestyles and risk of obesity in offspring: a prospective cohort study in China
Authors: Ye Qi, Rongxia Lv, Mengjia Zhao, Yuhui Huang, Yaodan Zhang, Hangrui Zhang, Peige Song, Zhihui Li, Peng Jia, Huanmei Zhang, Zhenyu Yang, Jianqiang Lai, Changzheng Yuan
Journal: The Lancet Global Health (2023)
Periconceptional diet and the risk of gestational diabetes in south Indian women: findings from the BAngalore Nutrition Gestational diabetes LiFEstyle Study (BANGLES)
Authors: Anvesha Mahendra, Sarah H Kehoe, Kalyanaraman Kumaran, G V Krishnaveni, Nalini Arun, Padmaja Pidaparthy, Prakash Kini, Unaiza Taskeen, Caroline H D Fall
Journal: The Lancet Global Health (2023)

BackgroundGestational diabetes can predispose two generations—a mother and her child—to a higher risk of obesity and type 2 diabetes. Culture-specific strategies to prevent gestational diabetes are required. BANGLES investigated the associations between women's periconceptional diet and gestational diabetes risk.MethodsBANGLES was a prospective observational study (n=785), in which women of various socioeconomic status were recruited at 5-16 weeks' gestation in Bangalore, India. Periconceptional diet was recalled at recruitment, using a validated 224-item food frequency questionnaire, that was reduced to 21 food groups for the food group–gestational diabetes analysis, and 68 food groups for the principal component analysis for a diet pattern–gestational diabetes analysis. Diet–gestational diabetes associations were examined using multivariate logistic regression, adjusting for a priori confounders determined from the literature. Gestational diabetes was assessed by a 75 g oral glucose tolerance test at 24–28 weeks' gestation, applying 2013 WHO criteria.FindingsWomen who consumed whole-grain cereals (adjusted odds ratio [OR] 0·58, 95% CI 0·34–0·97, p=0·03); had moderate egg consumption (>1–3 times per week) compared with less than once per week (adjusted OR 0·54, 95% CI 0·34–0·86, p=0·01); and a higher weekly intake of pulses and legumes (adjusted OR 0·81, 95% CI 0·66–0·98, p=0·03), nuts and seeds (adjusted OR 0·77, 95% CI 0·63–0·94, p=0·01), and fried and fast food (adjusted OR 0·72, 95% CI 0·59–0·89, p=0·002) had a lower gestational diabetes. None of these associations was significant after correction for multiple testing. A high-diversity, urban diet pattern characterised by diverse home-cooked and processed foods and associated with older, affluent, educated, urban women was associated with a lower risk (adjusted OR 0·80, 95% CI 0·64–0·99, p=0·04). BMI was the strongest risk factor for gestational diabetes and possibly mediated the diet pattern–gestational diabetes associations.InterpretationThe same food groups that were associated with a lower gestational diabetes risk were components of the high-diversity, urban diet pattern. One healthy diet pattern might not be relevant to India. Findings support global recommendations to encourage women to attain a healthy pre-pregnancy BMI, increase diet diversity to prevent gestational diabetes, and have policies to increase food affordability.FundingSchlumberger Foundation.
Environmental determinants of childhood obesity: a meta-analysis
Authors: Peng Jia, Yuanyuan Shi, Qi Jiang, Shaoqing Dai, Bin Yu, Shuhan Yang, Ge Qiu, Shujuan Yang
Journal: The Lancet Global Health (2023)

BackgroundThe increasing prevalence of childhood obesity has contributed to the growing global burden of chronic diseases over the life course, which has been largely attributed to obesogenic environments. This giant-scale review was done to translate existing obesogenic environmental studies into evidence-based governance for fighting childhood obesity and promoting life-course health.MethodsFollowing a standard strategy of literature search and inclusion, all obesogenic environmental studies, published since the inception of the electronic databases, were reviewed to identify the evidence on associations with childhood obesity of 16 obesogenic environmental factors, including 10 built environmental factors or indices (ie, land-use mix, street connectivity, residential density, speed limit, urban sprawl, and access to green space, public transport, bike lanes, sidewalks, and neighbourhood aesthetics) and six food environmental factors (ie, access to convenience stores, supermarkets, grocery stores, full-service restaurants, fast-food restaurants, and fruit and vegetable markets). A meta-analysis was conducted to quantify the influence of each factor with sufficient studies on childhood obesity.FindingsA total of 24 155 search results were found and filtered, with 457 studies included in the analysis. All built environmental factors, except speed limit and urban sprawl, were negatively associated with childhood obesity by encouraging physical activity while discouraging sedentary behaviours; the access to all food venues, except convenience stores and fast-food restaurants, was negatively associated with childhood obesity by encouraging their healthy eating behaviours. There were some globally consistent associations, such as between greater access to fast-food restaurants in the neighbourhood and more fast-food consumption, between better access to bike lanes and more physical activity, between better access to sidewalks and reduced sedentary behaviours, and between greater access to green space and more physical activity and less TV or computer screen time.InterpretationFindings have formed the unprecedentedly inclusive evidence for policy making and the establishment of the future research agenda regarding the obesogenic environment.FundingNational Natural Science Foundation of China, Chengdu Technological Innovation R&D Project, Sichuan Provincial Key R&D Program, and Wuhan University Specific Fund for Major School-level Internationalization Initiatives.
An intergenerational life-course approach to address early childhood obesity and adiposity: the Healthy Life Trajectories Initiative (HeLTI)
Authors: Kalyanaraman Kumaran, Catherine Birken, Jean-Patrice Baillargeon, Cindy-Lee Dennis, William D Fraser, Hefeng Huang, Jianxia Fan, Stephen Lye, Stephen G Matthews, Shane A Norris
Journal: The Lancet Global Health (2023)

BackgroundInteractions between genes and early-life exposures during conception, fetal life, infancy, and early childhood have been shown to affect an individual's health later in life. Maternal undernutrition and obesity, gestational diabetes, and impaired growth in utero and in early life are associated with adiposity and overweight and obesity in childhood, which are risk factors for poor health trajectories and non-communicable diseases. In Canada, China, India, and South Africa, 10–30% of children aged 5–16 years are overweight or obese.MethodsThe application of developmental origins of health and disease principles offers a novel approach to prevention of overweight and obesity and reduction of adiposity by delivering integrated interventions across the life course, starting before conception and continuing through early childhood. The Healthy Life Trajectories Initiative (HeLTI) was established in 2017 through a unique collaboration between national funding agencies in Canada, China, India, South Africa, and WHO. The aim of HeLTI is to evaluate the effect of an integrated four-phase intervention starting preconceptionally and continuing through pregnancy, infancy, and early childhood on reducing childhood adiposity (fat mass index) and overweight and obesity, and optimising early child development, nutrition, and other healthy behaviours.FindingsApproximately 22 000 women are being recruited in Shanghai (China), Mysore (India), Soweto (South Africa), and across various provinces of Canada. Women who conceive (an expected 10 000) and their children will be followed up until the child reaches the age of 5 years.InterpretationHeLTI has harmonised the intervention, measures, tools, biospecimen collection, and analysis plans for the trial to be run across four countries. HeLTI will help establish whether an intervention aimed at addressing maternal health behaviours, nutrition, and weight; providing psychosocial support to reduce maternal stress and prevent mental illness; optimising infant nutrition, physical activity, and sleep; and promoting parenting skills can reduce the intergenerational risk of excess childhood adiposity and overweight and obesity across diverse settings.FundingCanadian Institutes of Health Research; National Science Foundation of China; Department of Biotechnology, India; and South African Medical Research Council.
Socioeconomic disadvantage and polygenic risk for high BMI magnify obesity risk across childhood: a longitudinal, population, cohort study
Authors: Jessica A Kerr, Dorothea Dumuid, Marnie Downes, Katherine Lange, Meredith O’Connor, Lukar Thornton, Suzanne Mavoa, Kate Lycett, Tim S Olds, Ben Edwards, Justin M O’Sullivan, Markus Juonala, David Burgner, Melissa Wake
Journal: The Lancet Global Health (2023)

BackgroundAcross the life course, socioeconomic disadvantage disproportionately afflicts those with genetic predispositions to inflammatory diseases. We describe how socioeconomic disadvantage and polygenic risk for high BMI magnify the risk of obesity across childhood, and using causal analyses, explore the hypothetical impact of intervening on socioeconomic disadvantage to reduce adolescent obesity.MethodsData were drawn from a nationally representative Australian birth cohort, with biennial data collection between 2004 and 2018 (research and ethics committee approved). We generated a polygenic risk score for BMI using published genome-wide association studies. We measured early-childhood disadvantage (age 2–3 years) with a neighbourhood census-based measure and a family-level composite of parent income, occupation, and education. We used generalised linear regression (Poisson-log link) to estimate the risk of overweight or obesity (BMI ≥85th percentile) at age 14–15 years for children with early-childhood disadvantage (quintiles 4–5) versus average (quintile 3) and least disadvantage (quintiles 1–2), for those with high and low polygenic risk separately.FindingsFor 1607 children (n=796 female, n=811 male; 31% of the original cohort [N=5107]), polygenic risk and disadvantage were both associated with overweight or obesity; effects of disadvantage were more marked as polygenic risk increased. Of children with polygenic risk higher than the median (n=805), 37% of children living in disadvantage at age 2–3 years had an overweight or obese BMI by adolescence, compared with 26% of those with least disadvantage. For genetically vulnerable children, causal analyses indicated that early neighbourhood intervention to lessen disadvantage (to quintile 1–2) would reduce risk of adolescent overweight or obesity by 23% (risk ratio 0·77; 95% CI 0·57–1·04); estimates for improving family environments were similar (0·59; 0·43–0·80).InterpretationActions addressing socioeconomic disadvantage could mitigate polygenic risk for developing obesity. This study benefits from population-representative longitudinal data but is limited by sample size.FundingAustralian National Health and Medical Research Council.
Parental lifestyle patterns around pregnancy and risk of childhood obesity in four European birth cohort studies
Authors: Marion Lecorguillé, Mireille Schipper, Aisling O’Donnell, Adrien M Aubert, Muriel Tafflet, Malamine Gassama, Alexander Douglass, James R Hébert, Cecily Kelleher, Marie-Aline Charles, Catherine M Phillips, Romy Gaillard, Sandrine Lioret, Barbara Heude
Journal: The Lancet Global Health (2023)

BackgroundA high prevalence of excess weight in children younger than 5 years suggests the involvement of early-life risk factors. The preconception and pregnancy periods are crucial stages for the implementation of interventions to prevent childhood obesity. Most studies so far have evaluated the effects of early-life factors separately, with only a few investigating the combined effect of parental lifestyle factors. Our objective was to fill the literature gap regarding parental lifestyle factors in the preconception and pregnancy periods and to study their association with the risk of overweight in children after the age of 5 years.MethodsWe harmonised and interpreted data from four European mother–offspring cohorts (EDEN [comprising 1900 families], Elfe [comprising 18 000 families], Lifeways [comprising 1100 families], and Generation R [comprising 9500 families]). Written informed consent was obtained from parents of all involved children. Lifestyle factor data collected through questionnaires comprised parental smoking, BMI, gestational weight gain, diet, physical activity, and sedentary behaviour. We applied principal component analyses to identify multiple lifestyle patterns in preconception and pregnancy. Their association with child BMI z-score and risk of overweight (including obesity, overweight and obesity, as defined by the International Task Force reference) between the ages of 5 and 12 years were assessed using cohort-specific multivariable linear and logistic regression models (adjusted for confounders including parental age, education level, employment status, geographic origin, parity, and household income).FindingsAmong the various lifestyle patterns identified in all cohorts, the two that better explained variance were high parental smoking plus low maternal diet quality or high maternal sedentary behaviour, and high parental BMI plus low gestational weight gain. Overall, we observed that patterns characterised by high parental BMI, smoking, low-quality diet, or sedentary lifestyle before or during pregnancy were associated with higher BMI z-scores and risk of overweight and obesity in children aged 5–12 years.InterpretationOur data contribute to a better understanding of how parental lifestyle factors might be associated with the risk of childhood obesity. These findings are valuable to inform future family-based and multi-behavioural child obesity prevention strategies in early life.FundingEuropean Union's Horizon 2020 under the ERA-NET Cofund action (reference 727565) and European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL, EndObesity).
Effectiveness and co-benefits of a telephone-based intervention in reducing obesity risk of children aged 2–4 years: findings from a pragmatic randomised controlled trial during the COVID-19 pandemic in Australia
Authors: Li Ming Wen, Sarah Taki, Huilan Xu, Philayrath Phongsavan, Chris Rissel, Alison Hayes, Louise A Baur
Journal: The Lancet Global Health (2023)
The voices of children on movement behaviours: implications for promoting international guidelines to support obesity-prevention efforts
Authors: Katharina E Kariippanon, Nicolas Aguilar-Farias, Asmaa el Hamdouchi, Guan Hongyan, Himangi Lubree, Anthony D Okely, Mark S Tremblay, Catherine E Draper
Journal: The Lancet Global Health (2023)

BackgroundAs a key factor for the prevention of childhood obesity, WHO recommends a specific balance of movement behaviours (ie, physical activity, sedentary behaviour, and sleep) across the 24-h day for children younger than 5 years. Substantial evidence underpins our understanding of the benefits for healthy growth and development; however, little is known about young children's experiences and perceptions, and whether context-specific factors that might influence movement behaviours differ across the globe.MethodsAcknowledging children's agency as knowledgeable informants on matters affecting their lives, children aged 3–5 years from communities and preschools in urban and rural Australia, Chile, China, India, Morocco, and South Africa, were interviewed. Discussions were based on a socioecological framework of the multifactorial, complex influences on young children's movement behaviours. Prompts were adapted to ensure relevance across diverse study sites. Ethics approval and guardian consent were obtained, and the Framework Method used for analysis.Findings156 children (101 [65%] from urban areas, 55 [45%] from rural areas; 73 [47%] female, 83 [53%] male) shared their experiences, perceptions, and preferences related to movement behaviours and the barriers and enablers of outdoor play. Physical activity, sedentary behaviour, and to a lesser degree screen time occurred predominantly through play. Barriers to outdoor play included weather, air quality, and safety concerns. Sleep routines varied considerably and were influenced by room or bed sharing. Screen use was ubiquitous, presenting a challenge to meeting recommendations. The effect of daily structure, degree of autonomy, and interactions were consistent themes, and differences in how these factors influenced movement behaviours across study sites were evident.InterpretationThe findings highlight that although movement behaviour guidelines are universal, contextual realities need to be considered in how socialisation and promotion of the guidelines are enacted. How young children's sociocultural and physical environments are constructed and influenced can foster or disrupt healthy movement behaviours, which might have implications for childhood obesity.FundingBeijing High Level Talents Cultivation Project for Public Health Academic Leader; Beijing Medical Research Institute (Public service development and reform pilot project); British Academy for the Humanities and Social Sciences; KEM Hospital Research Centre; Ministry of Education and Universidad de La Frontera (Innovation in Higher Education Program); and National Health and Medical Research Council (Investigator Grant Leadership Fellow, Level 2).